The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 pg i.v.). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 microg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% post-treatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5+/-1.76 mm pre-treatment vs 21.6+/-2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7+/-288.5 pmol/l pre-treatment vs 986.4+/-382.1 pmol/l post-treatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.
PMID 11508781 11508781 DOI 10.1007/BF03343880 10.1007/BF03343880 Fulghesu et al. 2001, Fulghesu 2001
Cite this article
Fulghesu, A. M., Ciampelli, M., Belosi, C., Apa, R., Guido, M., Caruso, A., Mancuso, S., & Lanzone, A. (2001). Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study. Journal of endocrinological investigation, 24(7), 483-490. https://doi.org/10.1007/BF03343880
Fulghesu AM, Ciampelli M, Belosi C, Apa R, Guido M, Caruso A, et al. Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study. J Endocrinol Invest. 2001;24(7):483-490. doi:10.1007/BF03343880
Fulghesu, A. M., et al. "Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study." Journal of endocrinological investigation, vol. 24, no. 7, 2001, pp. 483-490.
Recent data indicate that an altered opioid tone could be involved in the LH hypersecretion and metabolic alterations seen in polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the presence of a common mechanism of action of opioids on altered insulin and gonadotropin release in patients suffering from PCOS. Twenty-eight women affected by PCOS and 8 normal ovulatory women were studied; an oral glucose tolerance test (OGTT) and GnRH tests were performed during the follicular phase before and after 6 weeks of naltrexone treatment (50 mg/day, orally). Plasma levels of sex hormone-binding globulin and steroids were assayed in the basal samples, whereas FSH and LH were analyzed during the GnRH stimulus. Insulin and glucose were assayed by the OGTT. Based on the insulinemic response to OGTT, 17 women were classified as hyperinsulinemic and 11 as normoinsulinemic. No difference in glucose and hormone plasma concentrations was observed before and after naltrexone treatment in both groups. Only basal sex hormone-binding globulin values were higher in normoinsulinemic compared to hyperinsulinemic subjects. Administration of the opioid antagonist significantly reduced the insulin response to OGTT only in the hyperinsulinemic group. No difference were found in the LH increment after the GnRH stimulus in both group of patients before treatment; on the contrary, naltrexone administration reduced the LH response to GnRH in hyperinsulinemic women but failed to be effective in normoinsulinemic subjects. Only 5 patients showed no concordance of drug-induced changes in insulin and LH secretion. In control subjects, naltrexone failed to have any effect on insulin or LH secretion. These data support the involvement of endogenous opioids in the regulation of insulin and LH secretion in a specific group of PCOS patients exhibiting an exaggerated insulin response to OGTT.
Fulghesu AM et al., 1993·Obstetrics and gynecology
To evaluate the involvement of endogenous opiates in the pathophysiology of the hyperinsulinism in patients affected by polycystic ovary disease by administering naloxone and naltrexone. We also studied the hormonal status following long-term opioid antagonist administration. Twenty-one women affected by polycystic ovary disease participated in the study. An oral glucose tolerance test (GTT) was performed at baseline and repeated after short-term naloxone infusion and after 6 weeks of naltrexone administration. Plasma glucose and insulin levels were evaluated in all samples. Gonadotropins, sex hormone-binding globulin, and androgen levels were determined initially and after the naltrexone treatment. None of the patients showed any alteration of glucose tolerance. Based on the insulin response to the GTT, the patients were classified as normo- or hyperinsulinemic. Opioid antagonist administration significantly reduced the insulin response to the GTT in hyperinsulinemic patients, without affecting their glycemic levels. In normoinsulinemic patients, glucose plasma levels were increased whereas insulin levels were not modified by the treatments. Gonadotropin and androgen plasma concentrations were not modified after naltrexone administration. This work supports a role for the endogenous opiates in the regulation of exaggerated insulin secretion in patients with polycystic ovary disease. The reduction of insulin secretion failed to demonstrate any hormonal modification in such hyperandrogenized patients.
In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.
Practice Committee of the American Society for Reproductive Medicine and Practice Committee of the Society for Reproductive Endocrinology and Infertility, 2026·Fertility and sterility
Luteal phase deficiency (LPD) is a clinical diagnosis associated with abnormal luteal phase length of ≤10 days. Potential etiologies of LPD include inadequate progesterone duration, inadequate progesterone levels, or endometrial progesterone resistance. Luteal phase deficiency has been described in association with medical conditions, but also in fertile, normally menstruating women. Although progesterone is important for the process of implantation and early embryonic development, LPD has not been proven to be an independent entity causing infertility or recurrent pregnancy loss. Controversy exists regarding the multiple proposed measures for diagnosing LPD, and assuming it can be diagnosed accurately, whether treatment improves outcomes. This document replaces the document of the same name, last published in 2021 (Fertil Steril 2021;115(6):1416-23).